The use of therapeutic substances to treat and/or prevent disease, injury or disability is a cornerstone of modern human and animal related medicine.
In order for such therapeutic substances to have useful effect to a desired treatment area, the substances must be physically and/or chemically available to the treatment area, and must be available in a sufficient concentration to exert a beneficial biological effect.
As an alternative to conventional methods of delivery of therapeutic substances, transdermal delivery techniques have been developed so that a degree of site specificity is obtained and a desired concentration of therapeutic substance is achieved which is unaltered by digestion or blood chemistry. Transdermal delivery techniques also offer the possibility of high user compliance, ease of management, low toxicity and high cost effectiveness.
However, mammalian skin poses a significant barrier to entry for many therapeutic substances because the lipid bilayer of the stratum corneum skin layer generally only allows very small neutrally charged particles of the order of 1 nm to pass through. As such, transdermal delivery of many ions, drugs, macro molecules, DNA fragments, genes and therapeutic substances is problematic.
In one transdermal technique referred to as iontophoresis, an electrical energy gradient is used to charge a target molecule and an electrical voltage is employed to accelerate the charged target molecule towards a cell membrane adjacent the target area, the energy of the target molecule being sufficient to cause the target molecule to pass through the cell membrane.
However, due to the relatively high energy levels employed, significant residual cellular damage occurs to the skin which can manifest as localised burns, skin irritation and cellular fatigue. In addition, critical ionic structures of the target molecule can be inadvertently changed by the process.
A further transdermal delivery technique is referred to as electroporation. With this technique, successive pulses of 1 ms to 10 ms duration of the order of 100 to 200 volts are directly applied to a target skin area using probes.
However, as with the iontophoresis technique, since relatively high energy levels are used, significant cellular damage occurs. In addition, in view of the high voltages employed, electroporation is unsuitable to use in vivo and to date has been used only in vitro.
The barrier effect of the stratum corneum arises as a result of the intercellular lipid matrix which comprises long chain ceramides, free fatty acids, cholesterol and other lipids. The lipids are arranged into bilayers having hydrocarbon chains aligned to form an oily bilayer core and electrically charged or polar outwardly facing head groups. This produces a highly selective filter-like structure. In contrast to phospholipid bilayer membranes found elsewhere in the body, the composition of the stratum corneum lipid bilayers is a much more rigid and ordered structure. As a consequence, the barrier to penetration of the stratum corneum by therapeutic substances is much greater compared to the corresponding barriers to penetration produced by other body membranes.
Therapeutic substance delivery techniques such as iontophoresis and electroporation rely on introducing sufficient energy to the stratum corneum to break up the inherent structure of the lipid bilayer, which disrupts the hydrophilic-hydrophobic orientation of the bilayer and creates regions of random orientation through which some substances may be introduced. Disruption of the dermal barrier effect in this way is unpredictable and provides little control over the rate of drug delivery.
In the claims of this application and in the description of the invention, except where the context requires otherwise due to express language or necessary implication, the words “comprise” or variations such as “comprises” or “comprising” are used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.